The present invention relates to novel compounds, pharmaceutical compositions and methods of use for the treatment of diseases in which 5-lipoxygenase enzyme activity contributes to the pathological condition. Thus, the novel compounds of the present invention have activity useful for treating asthma, allergies, cardiovascular diseases, migraines, psoriasis, immunoinflammatory conditions, and as cytoprotective agents.
More particularly the novel compounds having the formula I as defined below inhibit 5-lipoxygenase enzymes. Lipoxygenase pathway products such as the leukotrienes B4, C4, D4, and E4, 5-hydroxyeicosatetraenoic acid, 5-hydroperoxyeicosatetraenoic acid, and 12-hydroxyeicosatraenoic acid are related to the above described conditions. Specific conditions for use of the present novel lipoxygenase-inhibiting compounds, pharmaceutical compositions thereof and the novel method of use in accordance with the present invention include allergy; asthma; arthritis; skin disorders including psoriasis and acne; inflammation--including inflammatory bowel diseases or pain; and cardiovascular disorders including myocardial ischemia and infarction, angina, arrhythmias, stroke, migraine and atherosclerosis.
Itokawa, H. et al, "Synthesis of Diarylheptanoids and Assessment of Their Pungency," Chem. Pharm. Bull., 31, 2491 (1983) and "A Pungent Principle from Alpina Oxyphylla," Phytochemistry, 21, 241 (1982) disclose compounds: ##STR1## wherein Q.sub.1 and Q.sub.2 are independently hydrogen, hydroxy or methoxy, correlating structure and pungency with previously published pain-producing experiments on capsaicin congeners.
European Patent Application 163270A also discloses analogs of compound A.
Itokawa, H. et al, "Two New Diarylheptanoids from Alpinia Offcinarum Hance," Chem. Pharm. Bull., 29(8) 2383-5 (1981) disclose a compound from those of formula B above as a fraction of an extract which extract was used in Chinese medicine to relieve gastrointestinal disorders as well as fractions of which were known to contract the ileum of guinea pigs. Further, prostaglandin-biosynthesis inhibition having use as an antiinflammatory, antipyretic, analgesic or antiarteriosclerotic is disclosed in J5 9098-026-A (Derivent Abstract No. 84-178335/29) for the compound C as follows: ##STR2## wherein Q.sub.1 and Q.sub.1 are within the groups defined above therefor and Q.sub.2 is hydrogen or together with Q.sub.4 is ##STR3## Q.sub.5 and Q.sub.1 are hydrogen, optionally form a double bond between the 5- and 4-position carbon or together are ##STR4##
Finally, European Patent Application 149,242 discloses a compound of formula D: ##STR5## in which Q.sub.7 is hydrogen, alkyl, COQ.sub.9 or CONHQ.sub.9 wherein Q.sub.9 is an aliphatic or an aromatic group, R is alkyl or aralkyl, and the phenyl to which ##STR6## attaches may be substituted at the 2-, and/or 4-position by alkyl or chlorine and at the 3-position by alkyl or OQ' wherein Q' is alkyl, cycloalkyl or aralkyl. The compounds of formula D are said to be useful as lipoxygenase inhibitors.
However, the present novel compounds, pharmaceutical compositions and novel methods of using compounds as defined in the present invention are combinations of substituents on various moieties that are not taught or are unobvious from the very limited disclosures of the above references. The compounds of the limited disclosures are excluded herein.
Of lesser interest are diaryl containing compounds linked by carbons having 2 alternating oxygen containing carbons. These compounds are related to curcumin and are disclosed in the European Patent Application 149,242 noted above; by Rao, et al in "Antiinflammatory Activity of Curcumin Analogues," Indian J. Med. Res., 75 574-8 (April 1982), and by Pabon, "A Synthesis of Curcumin and Related Compounds," Recueil, 83 379-386 (1964).